Carbon Monoxide Releasing Molecule (CORM)‐Derived CO Modulates Endothelial Cell Pro‐Adhesive Phenotype By Interfering With Nuclear Factor kappa B (NFκB) Activation

Recently it has been shown that CO, a bi‐product of inducible heme oxygenase (HO‐1) can modulate inflammation. However, the mechanisms of CO‐anti‐inflammatory activity are not fully understood yet. In this study we assessed the effects and potential mechanisms of tricarbonyldichlororuthenium (II) dimmer (CORM‐2)‐liberated CO in an experimental model of sepsis. Sepsis in mice was induced by cecal ligation and perforation (CLP; 24 hrs). CORM‐2 (8mg/kg; i.v.) was administrated immediately after induction of CLP. PMN accumulation (MPO assay) was assessed in mice lung, heart and liver. In in vitro experiments human umbilical vein endothelial cells (HUVEC) were stimulated with LPS (10 μg/ml) for 4 hrs in the presence or absence of CORM‐2 (10–200 μM). Subsequently, activation of NFkB, an inflammation‐relevant transcription factor, along with the surface levels of ICAM‐1, E‐selectin and PMN adhesion to HUVEC were assessed. The obtained results indicate that treatment of septic mice with CORM‐2 attenuated PMN accumulation in the lung, heart and liver. In parallel, CORM‐2 prevented activation of NFκB (EMSA) in LPS‐stimulated HUVEC. This was accompanied by a decrease in surface levels of ICAM‐1, E‐selectin and subsequent PMN adhesion to HUVEC. Taken together these findings indicate that CORM‐released CO modulates inflammation by interfering with NFκB activation and therefore suppressing endothelial cell pro‐adhesive phenotype (HSFO‐NA5580 and MOP‐68848).